The hippocampus is susceptible to both physiological (the theta rhythm) and pathophysiological (epileptiform activity) forms of neuronal synchronization. This proposal intends to examine the synaptic mechanisms involved in the generation of abnormal epileptiform activity in the hippocampal slice preparation. The hippocampal slice can not have a behavioral seizure, but it can display abnormal neuronal synchronization that resembles ictal and interictal epileptiform discharges recorded in vivo. The slice preparation provides the opportunity to study the cellular physiology of epileptiform activity and permits the alteration of the extracellular environment. Intracellular studies have demonstrated the importance of synaptic mechanisms in the generation of the paroxysmal depolarizing shift (PDS), the intracellular correlate of the interictal discharge, which can be produced by reduction of synaptic inhibition mediated by GABA or the reduction of certain potassium currents. The PDS generated by either class of convulsants is comprised of synchronously occurring synaptic potentials and represents a network phenomenon. The goal of this proposal is to unravel the role of synaptic transmission in the expression and modulation of patterns of epileptiform activity (interictal and ictal). Experiments will use intracellular voltage- and current-clamp recording techniques and extracellular monitoring of the neuronal population response. The first specific aim is to relate the afterhyperpolarization that follows the PDS to the characteristics of spontaneous epileptiform activity as defined by the rate and duration of interictal discharges and the generation of ictal-like discharges. The second specific aim is to determine the contribution of synaptic transmission, particularly inhibitory synaptic transmission, in the generation of ictal patterns of synchronization. The third specific aim is to characterize the recurrent excitatory synaptic connections in the CA3 subfield after lesioning hippocampal afferents carried by the fornix (primarily commissural and cholinergic afferents), and define how the sequela of the lesion may increase the propensity for epileptiform synchronization. The underlying premise of this proposal is that by understanding epileptiform activity in the hippocampus, not only will the basis for clinical therapy of epilepsy be better designed, but also the synaptic mechanisms that contribute to normal synchronized neuronal activity may be better understood.